HSF1 is the key transcriptional regulator of heat shock protein synthesis that defines the response to hyperthermia, and affects resistance to certain conventional drugs and radiation. Recently, based on both model and population studies, Hsf1 has emerged as a major factor in breast cancer development. We have demonstrated that HSF1 plays an essential role in malignant transformation and maintenance of cancer cells by controlling oncogene-induced senescence, and tumor angiogenesis. To advance our understanding of oncogenesis and radiation resistance, and to rationally target Hsf1 in specific cancer types, here we will address fundamental questions: (1) what are the key mechanisms of Hsf1 activation in Her2-positive cancer, (2) how does Hsf1 affect development and progression of Her2-positive breast cancer, and (3) what is the role of HSF1 in resistance to ionizing radiation. Aim 1 will address how HSF1 is regulated in mammary tumorigenesis. We will elucidate whether Hsf1 is constitutively activated in tumors because of aneuploidy-associated proteotoxicity by co-opting the signal transduction pathways observed in the heat shock response, or as a part of conventional HER2- mediated cancer signaling. In Aim 2, we will clarify how Hsf1 enters functional complexes in response to Her2, and affects global transcription. We will then elucidate the role of transcription mediated by HSF1 in the cancer cells, establishing HSF1 as a cancer stem cell factor, a player in epithelial/mesenchymal transition and a determinant of tumor metastasis (Aim 3). Finally, we will establish how Hsf1 determines cancer responses to ionizing radiation by testing a hypothesis that radiation resistance is linked to Hsf1-mediated control of cancer stem cells.